Overcoming the obstacles of eliciting broadly neutralizing antibodies (NAb) to HIV-1 will be a major step[unreadable] forward to developing a successful AIDS vaccine. The long-term objectives of project 2 are to design,[unreadable] evaluate and select novel HIV-1 enveloped based immunogens which are capable of inducing broad[unreadable] neutralizing antibodies which will have a protective effect in vaccinated individuals. The challenge and[unreadable] reason for this B-cell epitope focused approach is that HIV-1 has developed multiple mechanisms to shield[unreadable] itself and evade the antiviral effects of many antibodies. By far most host antibodies directed to the envelope[unreadable] (Env) of HIV-1 are ineffective in eliciting broad Nab responses. There are however several conserved B-cell[unreadable] epitopes which are rarely exposed, but when recognized by the host are able to elicit a broad Nab response.[unreadable] Here we aim to develop vaccine immunogens which together will focus the antibody response to highly[unreadable] conserved Env epitopes. Specifically our aims are to:[unreadable] 1. To improve the presentation of conformational Nab B-cell epitopes (mimotopes) for optimal presentation in[unreadable] vivo by; a) Combinatorial Synthesis and "Click" chemistry through direct collaboration and interaction with[unreadable] Core D, and, b) Engineered virus-like particles (VLPs) expressing Nab epitopes. Experience in VLPs[unreadable] expressing HIV peptides will include p55 Gag as well as Hepatitis B particles (Univ Regensburg, this[unreadable] project).[unreadable] 2. To identify the optimal vaccine platforms (protein, peptide, and/or viral vector) and regimen for either[unreadable] priming or boosting conformationaly dependent epitope specificities. This will be facilitated by close[unreadable] interaction with the vaccine technologies core (B) as well as complementary Env structures developed in[unreadable] projects 1 and 3.[unreadable] 3. To determine how many Nab peptide epitopes can optimally be combined in a prime boost immunization[unreadable] protocol to ultimately generate robust neutralizing antibody responses in an outbred population, evaluated[unreadable] first in rabbits and subsequently more stringently in non-human-primates models (Core C).[unreadable] 4. To determine "proof of principle" protective efficacy of these optimized mimotope-based vaccine regimens[unreadable] in the SHIV rhesus macaque vaccine challenge model. The best combination of NAb B-cell epitope[unreadable] presenting structures and delivery systems will be revealed in heterologous and mucosal challenge studies.